This research aims to examine both operant [(e.g., DRL schedule, i.v. self-administration (S-A)] and unconditioned behaviors (e.g., locomotor activity) to study the consequences of cocaine and d-methamphetamine (d-MA) pharmacokinetics (PK) on their respective pharmacodynamics (PD). Although the two stimulants exhibit similar pharmacological effects and abuse liability, they differ distinctly in PK profiles; cocaine is short acting and d- MA is long acting. The PK/PD modeling approach will be used to describe and predict the time course of the pharmacological response for the two stimulants to investigate whether PK play a key role in drug addiction and dependence. Both low- and high- rate operant behaviors, which model two activity levels routinely seen in humans, will be used to determine whether any observed concentration-effect relation is generalizable to a wide range of behavior patterns. The integration of PK and PD allows partitioning of the response into PK and PD components and the prediction of the time course of an emerging PD event, e.g., the development of sensitization/tolerance (S/T). Experiments with rats implanted with dual catheters (jugular vein and femoral artery) will determine the concentration-effect relations after constant-rate i.v. infusion using various dose regimens (e.g., acute, repeated, binge, escalating dose-binge pattern). The time course of S/T development can be readily characterized quantitatively by PD model(s) under various steady-state cocaine or d-MA concentrations (CSS) in well-defined PK conditions. Furthermore, the effects of rate of rise in drug concentration to a CSS level on the rate and extent of S/T development will be investigated. S/T is considered an important component in the behavioral model of drug addiction. The identification of critical time points is crucial for the investigation of the underlying mechanism(s) of S/T and may lead not only to the development of rational pharmacotherapies for drug addiction but also to the implementation of intervention at a vulnerable stage. Studies will also focus on whether and how PK factors (e.g., fraction of cocaine protein binding) effect the enhanced i.v. drug S-A under a food-limited regimen, which in turn may identify factors that produce vulnerability to addiction. Caffeine is known to potentiate the reinforcing and other effects of cocaine. The role of PK will be investigated to explore the mechanism of the interaction between caffeine and cocaine under acute- and chronic-dose regimens before other PD mechanism(s) are inferred.